1. Field of the Invention
The present invention pertains to certain substituted guanidines, and methods of treatment and pharmaceutical compositions that utilize or comprise one or-more such guanidines.
2. Background
Neurons of the mature central nervous system (xe2x80x9cCNSxe2x80x9d) are highly specialized and in general do not replace themselves. Consequently, death or degeneration of cells in the nervous system can have far more serious consequences than cell death or degeneration in other organs. Abnormal neuronal death can be rapid and widespread as in traumatic brain injury, or can occur over many years among very specific populations of neurons as in chronic neurodegenerative diseases.
Substantial evidence now points to pernicious overactivity of normal neurotransmitter systems as a contributory mechanism in many instances of pathological neuronal degeneration. In particular, overstimulation of neuronal receptors for L-glutamate, the brain""s most prevalent excitatory amino acid (xe2x80x9cEAAxe2x80x9d) neurotransmitter, has been recognized as a causal or exacerbating factor in several acute neurological disorders, and has been proposed to underlie a number of chronic neurodegenerative diseases as well [Choi, D. W., Neuron., 1:623 (1988); Choi, D. W., Cerebrov. and Brain Metab. Rev., 2:105 (1990); Albers, G. W., et al., Ann. Neurol., 25:398 (1989)]. Indeed, it is believed that glutamate neurotoxicity is involved in acute injury to the nervous system as observed with seizure, hypoxia, hypoglycemia, and trauma, as well as in chronic degenerative diseases such as Huntington""s disease, olivopontocerebellar atrophy associated with glutamate dehydrogenase deficiency and decreased glutamate catabolism, amyotrophic lateral sclerosis/Parkinsonium-dementia, Parkinson""s disease, and Alzheimer""s disease [Choi, D. W., Neuron, 1:623-634 (1988); Choi, D. W., Cereb. Brain Met., Rev. 2:105-147 (1990); Courtier et al., Lancet, 341:265-268 (1993); Appel, S. H., Trends Neurosci., 16:3-5 (1993)].
In the mammalian brain, glutamate interacts with three major classes of receptors, i.e., N-methyl-D-aspartate (xe2x80x9cNMDAxe2x80x9d) receptors, non-NMDA receptors and metabotropic receptors [Watkins, J. D., et al., Trends Neurosci., 10:265 (1987); and Seeburg, TIPS, 141:297 (1993)]. While triggering distinctive postsynaptic responses, all three classes of glutamate receptors can act to Increase the intracellular concentration of free Ca2+ in nerve cells [A. B. MacDermott, Nature 321:519 (1986)]. Thus, binding of glutamate to the NMDA receptor opens a cation-selective channel that is markedly permeable to Ca2+, leading to a large and rapid increase in intracellular Ca2+. A subclass of non-NMDA receptors has been found to be linked to a Ca-permeable cation channel [Sommer, B., and Seeburg, P. H., Trends Pharmacol. Sci. 13:291-296 (1992)]. Although non-NMDA receptors are in most other instances linked to cation channels that largely exclude calcium, they can indirectly promote Ca2+ entry into neurons by depolarizing the cell membrane, which in turn opens voltage-activated Ca2+-channels. The so-called xe2x80x9cmetabotropic receptorxe2x80x9d, on the other hand, is not associated with an Ion channel but can promote the release of Ca2+ from intracellular stores via the second-messenger inositol triphosphate.
Irrespective of the triggering mechanism, prolonged elevation of cytosolic Ca2+ is believed to be a key event in the initiation of neuronal destruction. Adverse consequences of elevated intracellular Ca2+ include derangement of mitochondrial respiration, activation of Ca2+-dependent proteases, lipases and endonucleases, free radical formation and lipid peroxidation of the cell membrane [Choi, D. W., Neuron, 1:623-624 (1988)].
The NMDA subtype of excitatory amino acid receptors is strongly involved in nerve cell death which occurs following brain or spinal chord ischemia. Upon the occurrence of ischemic brain insults such as stroke, heart attack or traumatic brain injury, an excessive release of endogenous glutamate occurs, resulting in the over-stimulation of NMDA receptors. Associated with the NMDA receptor Is an ion channel. The recognition site, i.e., the NMDA receptor, is external to the ion channel. When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permitting a flow of cations across the cell membrane, e.g., Ca2+ and Na+ into the cell and K+ out of the cell. It is believed that this flux of ions, especially the influx of Ca2+ ions, caused by the interaction of glutamate with the NMDA receptor, plays an important role in nerve cell death [see, e.g., Rothman, S. M. and Olney, J. W., Trends in Neurosci., 10(7):299-302 (1987)]. Additionally, excessive excitation of neurons occurs in epileptic seizures and it has been shown that over-activation of NMDA receptors contributes to the pathophyslology of epilepsy [(Porter, R. J., Epilepsia, 30(Suppl. 1):S29-S34 (1989); and Rogawski, M. A., et al., Pharmacol. Rev., 42:224-286 (1990)].
Non-NMDA receptors constitute a broad category of postsynaptic receptor sites which, as is the case for NMDA receptors, are directly linked to ion channels. Specifically, the receptor sites are physically part of specific ion channel proteins. Non-NMDA receptors have been broadly characterized into two major subclasses based on compounds selective therefor: kainate receptors and AMPA/quisqualate receptors [see J. C. Watkins et al., Trends Neurosci., 10:265 (1987)]. AMPA is an abbreviation for xcex1-amino-3-hydroxyl-5-methyl-4-isoazole propionic acid. These subclasses may be categorized as xe2x80x9cnon-NMDAxe2x80x9d receptors.
Compared to NMDA receptors, non-NMDA receptors have received less pharmacological scrutinyxe2x80x94the existing antagonists are all competitivexe2x80x94and in vivo research In this area has been hampered by the lack of drugs that cross the blood-brain barrier. Nonetheless, in vivo studies have clearly demonstrate that non-NMDA receptor agonists can also be as excitotoxic, although longer exposures can be required. In addition, evidence from animal studies and from human epidemiological studies suggests that excitotoxicity mediated by non-NMDA receptors may be clinically important in certain pathologies. [see M. D. Ginsberg et al., Stroke, 20:1627 (1989)].
One such disorder is global cerebral ischemia or hypoxia, as occurs following cardiac arrest, drowning, and carbon monoxide poisoning. Transient, severe interruption of the cerebral blood supply and/or interruption of the delivery of oxygen to the brain of animals causes a syndrome of selective neuronal necrosis, in which degeneration occurs among special populations of vulnerable neurons (including neocortical layers 3, 5 and 6, pyramidal cells in hippocampal zones CA1 and CA3, and small and medium sized striatal neurons). The time course of this degeneration is also regionally variable, and can range from a few hours (striatum) to several days (hippocampus).
NMDA antagonists generally have not proven highly effective in animal models of global ischemia; indeed, it has been suggested that positive results obtained using NMDA antagonists may largely be the artifactual result of induction of hypothermia rather that due to direct inhibition of NMDA receptor-linked Ca entry into brain neurons [Buchan, A. et al., J. Neurosci., 11 (1991) 1049-1056]. In contrast, the competitive non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (xe2x80x9cNBQXxe2x80x9d) is dramatically effective in preventing delayed neuronal degeneration following transient forebrain ischemia in both gerbils and rats [M. J. Sheardown et al., Science, 247:571-574 (1990)].
At present, there is a critical need for effective treatments which limit the extent of nerve cell death following a stroke or traumatic brain injury. Recent advances in the understanding of the mechanisms underlying this nerve cell death have led to the hope that a drug treatment can be developed. Research and development efforts in this area have focussed on blocking the actions of glutamate that are mediated by the NMDA receptor-channel complex. Two approaches have been developed: competitive NMDA receptor antagonists [Choi D. W., Cerebrov. Brain Metab. Rev. 1:165-211 (1990); Watkins, J. C. and Olverman, H. J., Trends Neurosci., 10:265-272 (1987)] and blockers of the ion channel of the NMDA receptor-channel complex [Meldrum, B., Cerebrovascular Brain Metab. Rev. 2:27-57 (1987); Choi, D. W., Cerebrovascular Brain Metab. Rev. 2:105-147 (1987); and Kemp, J. A. et al., Trends Neurosci., 10:265-272 (1987)]. However, some toxicity with certain of the aforementioned agents has been reported has been reported [Olney, J. W. et al., Science. 244:1360-1362 (1989); Koek, W. and Colpaert, J., et al., J. Pharmacol. Exp. Ther., 252:349-357 (1990)].
Blockers of neurotransmitter release, in particular blockers of the release of glutamate, have also received some attention as potential neuroprotective agents (see Meldrum, B., Cerebrovascular and Brain Metab., Rev. 2: 27-57 (1990); Dolphin, A. C. Nature, 316:148-150 (1985)); Evans, M. C. et al., Neurosci. Lett., 83:287-292 (1987); Ault, B. and Wang, C. M., Br. J. Pharmacol., 87:695-703 (1986); Kaneko, T., et al., Arzneim-Forsch./Drug Res., 39:445-450 (1989); Malgouris, C., et al., J. Neurosci., 9:3720-3727 (1989); Jimonet, P. et al. BioOrgan. and Med. Chem. Lett., 983-988 (1993); Wahl, F. et al., Eur. J. Pharmacol., 230:209-214 (1993); Koek, J. W. and Colpaert, F. C., J. Pharmacol. Exp. Ther., 252:349-357 (1990); Kaneko, T. et al., Arzneim.-Forsch./Drug Res., 39:445-450 (1989)]. Certain compounds said to inhibit glutamate release also have been reported to show anticonvulsant activity [Malgouris, C., et al., J. Neurosci., 9: 3720-3727 (1989); Miller, A. A., et al., in New Anticonvulsant Drugs, Meldrum, B. S. and Porter R. J. (eds), London: John Libbey, 165-177 (1986)].
Calcium antagonists acting at L-type Ca channels such as nimodipine have been reported to act both as cerebral vasodilators [Wong, M. C. W. et al., Stroke, 24:31-36 (1989)], and to block calcium entry into neurons [Scriabine, A. Adv. Neurosurg., pp. 173-179 (1990)]. Modest improvement in the outcome of stroke has been observed in clinical trials [Gelmers, H. J. et al., N. Eng. J. Med., 318:203-207 (1988)]. While there are significant cardiovascular side effects, nimodipine appears less toxic In other respects than certain NMDA antagonists.
Antagonists of voltage-gated Na channels can exhibit neuroprotective properties. [Graham, S. H., et al., J. Cereb. Blood Flow and Metab., 13:88-97 (1993), Meldrum, B. S., et al., Brain Res., 593:1-6 and Stys, P. K., et al., J. Neurosci., 12: 430-439 (1992)]. In stroke, sustained hypoxia in the xe2x80x9ccore regionxe2x80x9d results from occlusion of the blood supply by a clot. As hypoxia develops, ATP depletion leads to an inability of the Na, K-ATPase to maintain the Ion gradients which generate the normal membrane potential of resting nerve cells. As the cell depolarizes and reaches the threshold for action potential firing, Na channels are activated. Stys et al. [Stys, et al., J. Neurosci., 12: 430-439 (1992)] recently reported the development of Na channel hyperactivity in anoxia of central white matter and demonstrate in vitro the neuroprotective effect of the Na channel blockers tetrodotoxin (TTX) and saxitoxin (STX).
The present invention provides therapeutically useful substituted guanidine compounds, including compounds that modulate, particularly inhibit, the release of a neurotransmitter such as glutamate, and methods of treatment comprising such compounds. Preferred compounds of the invention modulate, particularly inhibit, neurotransmitter (e.g., glutamate) release from ischemic neuronal cells, especially mammalian cells such as human neuronal cells. The compounds of the invention are useful for a number of therapeutic applications, including treatment of those diseases that result from modulation of a particular neurotransmitter system and that can be counteracted by one or more of the substituted guanidines of the invention which act either on the same or another class of neurotransmitters, and treatment of a variety of disorders of the nervous system and cardiovascular system, and of endocrine function.
In a first aspect, the present invention provides N,N-disubstituted guanidines of Formula I: 
wherein:
R and R1 are each independently substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being carbocyclic aryl, aralkyl, a heteroaromatic group or a heterocyclic group;
R2 and R3 each being independently selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted and unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, and substituted and unsubstituted aminoalkyl; and pharmaceutically acceptable salts thereof.
A preferred group of compounds of Formula I are N,N-disubstituted compounds of the following Formula IA: 
wherein R and R1 are as defined above for Formula I, and pharmaceutically acceptable salts thereof.
A further preferred group of compounds of Formula I are compounds of the following Formula IB: 
wherein R and R1 are as defined above for Formula I, and R2 and R3 each being independently selected from the group consisting of hydrogen, substituted and substituted alkyl having from 1 to about 20 carbon atoms, substituted and unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted and unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, and substituted and unsubstituted aminoalkyl, with at least one of R2 and R3 being other than hydrogen; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formulas I, IA or IB include those compounds where at least one, or more preferably both, of R and R1 is substituted or unsubstituted carbocyclic aryl or substituted or unsubstituted aralkyl or substituted or unsubstituted alkaryl. Preferred compounds of Formulas I, IA and IB include those compounds having substituents with 1 to about 6 carbon atoms, particularly R2 and/or R3 groups that have 1 to 6 carbon atoms. Particularly preferred R2 and R3 substituents of compounds of Formulas I, IA or IB include unsubstituted alkyl and heteroalkyl such as alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl and aminoalkyl. Preferred R and R1 groups include substituted and unsubstituted acenaphthyl, phenyl, biphenyl, naphthyl, fluorenyl and benzyl, particularly alkyl-substituted and alkoxy-substituted phenyl and benzyl. Particularly preferred R and R1 groups include straight and branched chain C1-8-alkyl substituted phenyl and benzyl such as tert-butylphenyl, tert-butylbenzyl, sec-butylphenyl, sec-butylbenzyl, n-butylphenyl, n-butylbenzyl, iso-butylphenyl, iso-butylbenzyl, pentylphenyl, pentylbenzyl, hexylphenyl, hexylbenzyl and the like; straight and branched chain C1-8-alkoxy (including haloalkoxy, i.e. alkoxy substituted by F, Cl, Br and/or I) substituted phenyl and benzyl such as butoxyphenyl, butoxybenzyl, pentoxyphenyl, pentoxybenzyl, hexoxyphenyl, hexoxybenzyl, trifluoromethoxyphenyl, trifluorobenzyl, fluoro and the like; alkaryl (including alkoxyaryl) substituted phenyl and benzyl, particularly substituted and unsubstituted benzyl and benzyloxy (especially xe2x80x94OCH2C6H5). Cycloalkyl and aryl (particularly carbocyclic aryl) such as substituted phenyl, benzyl and naphthyl are also preferred R and R1 groups such as biphenyl, phenylbenzyl (i.e. xe2x80x94CH2C6H4C6H5), cyclohexylphenyl, cyclohexylbenzyl and the like. Halo (i.e., F, Cl, Br and/or I) substituted R and R1 groups are also preferred including halo-substituted phenyl, naphthyl and benzyl.
In another aspect, the invention provides compounds of the following Formula II: 
wherein
R is selected from the group of fluorenyl, phenanthracenyl, anthracenyl and fluoranthenyl;
R1 is substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about carbon atoms, substituted or unsubstituted alkynyl having from 2 to 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 5 ring atoms, substituted or unsubstituted aralkyl having at least about 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
R2 and R3 are each independently hydrogen or a group as defined for R1 above; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula II include N,Nxe2x80x2-disubstituted compounds, i.e. where R2 and R3 are each hydrogen, as well as tri- and tetra-substituted compounds where one or both of R2 and R3 are other than hydrogen. Preferred R1 groups include cycloalkyl, particularly adamantyl, and carbocyclic aryl, particularly substituted or unsubstituted phenyl, naphthyl or acenaphthyl, more preferably substituted or unsubstituted phenyl or naphthyl, such as alkyl or alkoxy substituted phenyl or naphthyl. Alkyl such as methyl, ethyl or propyl is a preferred R2 or R3 group.
In a further aspect, the invention provides compounds of the following Formula III: 
wherein R and R1 are each independently substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aryloxy having from 6 to about 20 carbon atoms, substituted or unsubstituted aralkoxy having from 6 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least 5 ring atoms, substituted or unsubstituted aralkyl having at least 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
R2 and R3 are each independently hydrogen or a group as defined for R and R1 above, and preferably are each substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aminoalkyl, alkylthio or alkylsulfinyl; or R1 and R3 together form a ring having 5 or more ring members;
n and nxe2x80x2 independently are each equal to 1, 2, or 3;
X and Xxe2x80x2 are each independently a chemical bond (i.e., a bond between the guanidine nitrogen and R or R1), substituted or unsubstituted alkylene having from 1 to about 8 carbon atoms, substituted or unsubstituted alkenylene having from 2 to about 8 carbon atoms, or substituted or unsubstituted alkynylene having from 2 to about 8 carbon atoms, substituted or unsubstituted heteroalkylene having from 1 to about 8 carbon atoms, substituted or unsubstituted hateroalkenylene having 2 to about 8 carbon atoms, and substituted or unsubstituted heteroalkynylene having from 2 to about 8 carbon atoms, with at least one X and Xxe2x80x2 being other than a bond; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula III include those where X is substituted or unsubstituted alkylene or alkenylene having 1 to about 3 carbon atoms, particularly where X is a substituted or unsubstituted alkylene having 1 to about 6 carbon atoms, more preferably 1 to about 4 carbon atoms, as specified by the following Formula IIIA: 
wherein the groups R, R1, R2 and R3 are as defined above for Formula III, and the value n is equal to 1, 2 or 3; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula III include those where R and R1 together form a ring having 5 or more ring atoms, either with the guanidine nitrogen as the sole hetero atom or with one or more other N, O or S atoms as ring members, typically just one other N, O or S ring atom in addition to the guanidine N. Generally preferred is where R and R1 together form a ring having 5-7 ring atoms, e.g., forming the following substituted or unsubstituted rings: morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl and tetrahydroquinolinyl. Preferred substituents of such rings include e.g. C1-8alkyl, C1-8alkoxy and substituted and unsubstituted alkaryl, particularly substituted and unsubstituted benzyl.
Particularly preferred such compounds of Formula III are those of the following Formula IIIB: 
wherein R and R2 of said formula are each independently substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aryloxy having from 6 to about 20 carbon atoms, substituted or unsubstituted aralkoxy having from 6 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least 5 ring atoms, substituted or unsubstituted aralkyl having at least 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
n is 1, 2, or 3, and preferably is 1 or 2, more is preferably 1; W is a carbon atom, or N, O or S; m is an integer of from 0 to 5, and preferably is 1, 2 or 3, more preferably 0, 1 or 2.
X is substituted or unsubstituted alkylene having from 1 to about 8 carbon atoms, substituted or unsubstituted alkenylene having from 2 to about 8 carbon atoms, or substituted or unsubstituted alkynylene having from 2 to about 8 carbon atoms, substituted or unsubstituted heteroalkylene having from 1 to about 8 carbon atoms, substituted or unsubstituted heteroalkenylene having 2 to about 8 carbon atoms, and substituted or unsubstituted heteroalkynylene having from 2 to about 8 carbon atoms, and preferably X is substituted or unsubstituted alkylene, particularly alkylene having 1 to 2 carbon atoms;
each Y substituent is independently halogen, substituted or unsubstituted alkyl having 1 to about 10 carbon atoms, substituted or unsubstituted alkenyl having 2 to about 10 carbon atoms, unsubstituted alkynyl having 2 to about 10 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 10 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 10 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 10 carbon atoms, or substituted or unsubstituted carbocyclic aryl having about 6 or more ring members; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IIIB are those where R and R2 are each independently aryl, particularly substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl or substituted or unsubstituted acenaphthyl.
Especially preferred compounds of Formula IIIB are those where R and R2 are each substituted or substituted phenyl, such as sec-butylphenyl or tert-butylphenyl, particularly para-sec-butylphenyl or para-tert-butylphenyl, n is 1 and X is alkylene of one or two carbons. Particularly preferred are compounds of the following Formula IIIBB: 
wherein W is a carbon atom, or N, O or S;
each Y, each Yxe2x80x2 and each Yxe2x80x3 is each independently halogen, substituted or unsubstituted alkyl having 1 to about 10 carbon atoms, substituted or unsubstituted alkenyl having 2 to about 10 carbon atoms, unsubstituted alkynyl having 2 to about 10 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 10 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 10 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 10 carbon atoms, or substituted or unsubstituted carbocyclic aryl having about 6 or more ring members; n is 1 or 2, and each m, mxe2x80x2 and mxe2x80x3 is independently an integer of from 0 to 5, and preferably is each m, mxe2x80x2 and mxe2x80x3 is independently 0, 1, 2 or 3, more preferably 0, 1 or 2; and pharmaceutically acceptable salts thereof. Generally preferred compounds of Formulas IIIB and IIIBB are those where a Y group is bonded to the W ring member, particularly where W and Y together form a substituted carbon atom or N atom such as a C1-8alkyl or C1-8alkoxy substituted carbon or nitrogen ring atom. As will be of course understood by those skilled in the art, where m, mxe2x80x2 or mxe2x80x3 is 0, the corresponding ring would be xe2x80x9cfullyxe2x80x9d hydrogen-substituted. Specifically preferred compounds of Formula IIIBB include N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-Nxe2x80x2-(4-piperidinyl)guanidine; N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-Nxe2x80x2-(4-benzylpiperidinyl)guanidine; N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-Nxe2x80x2-(4-morpholinyl)guanidine; and N-(4-butoxyphenyl)-N-(4-tert-butylbenzyl)-Nxe2x80x2-(3,5-dimethyl-4-morpholinyl)guanidine.
A further group of preferred compounds of Formula III are defined the same as Formulas IIIB and IIIBB above, but where two Y substituents are taken together to form an aryl or alicyclic fused ring. Generally preferred is where the fused ring is a heterocyclic or carbocyclic aryl, particularly phenyl, naphthyl, 1,2,3,6-tetrahydroquinolinyl, thiomorpholinyl, pyrolindinyl, piperazinyl and the like, or a cycloalkyl such as cyclohexyl. A specifically preferred compound is N-(4-sec-butylphenyl)-N-(4-tert-butylbenzyl)-Nxe2x80x2-(1,2,3,4-tetrahydroisoquinolinyl)guanidine.
Preferred compounds of Formulas III, IIIA and IIIB include those where R and/or R1 is substituted or unsubstituted carbocyclic aryl, particularly substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl or substituted or unsubstituted acenaphthyl. Particularly preferred are compounds of Formula III and IIIA where R, R1 and R2 are each substituted or unsubstituted carbocyclic aryl, particularly substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl or substituted or unsubstituted acenaphthyl. Especially preferred are compounds of Formula IIIA where R, R1 and R2 are each such a substituted or unsubstituted carbocyclic aryl, R3 is hydrogen or C1-4 alkyl such as methyl or ethyl, and n is 1 or 2. Of those especially preferred compounds one or more of R, R1 and R2 is preferably substituted or unsubstituted phenyl e.g. C1-8alkyl-substituted phenyl such as sec-butylphenyl tert-butylphenyl and the like, halo-substituted phenyl, C1-8alkoxysubstituted phenyl such as butoxyphenyl or pentoxyphenyl or carbocyclic alkaryloxy-substituted phenyl such benzyloxyphenyl.
Preferred compounds of Formula III and IIIA also include N,Nxe2x80x2-disubstituted compounds, i.e. where R2 and R3 are each hydrogen, as well as tri- and tetra-substituted compounds where one or both of R2 and R3 are other than hydrogen. Preferred R1 and R3 groups include alkyl such as methyl, ethyl or propyl, and substituted alkyl, particularly haloalkyl such as C1-C8 or C1-C4 alkyl substituted by one or more F, Cl or Br. Alkylene and heteroalkylene are preferred X or Xxe2x80x2 groups, including those heteroalkylene groups containing 1 or 2 N, O, or S atoms as chain members. Particularly preferred X and Xxe2x80x2 groups of compounds of Formulas III, IIIA and IIIB include xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94 and xe2x80x94CH2CH(CH3)xe2x80x94. Preferred compounds of Formulas III and IIIA include those where each R and R1 group of a compound is bonded to the same carbon atom of the X or Xxe2x80x2 chain.
In a further aspect, compounds of the following Formula IV are provided: 
wherein
each R is independently halo, hydroxy, amino, nitro, substituted or unsubstituted alkyl having from 3 to about 10 carbon atoms and preferably from 4 to about 10 carbon atoms, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl having 3 to about 10 carbon atoms, or substituted or unsubstituted alkynyl having 3 to about 10 carbon atoms;
n is an integer of from 1 to 5, preferably from 1 to 3;
R1 is substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having 1 to about 20 carbon atoms, substituted or unsubstituted aryloxy having from 6 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least 5 ring atoms, substituted or unsubstituted aralkyl having at least 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
R2 and R3 are each independently hydrogen or a group as defined for R1 above; or R2 and R3 are taken together to form a substituted or unsubstituted alkylene linkage of from 2 to about 6 carbon atoms; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula IV include those where one or more R substituents is a branched group such as sec-butyl or tert-butyl, or where one or more R substituent is substituted or unsubstituted aralkoxy, particularly substituted or unsubstituted benzyloxy. The value n is preferably 1, 2 or 3. Para-substitution and meta-substitution of the phenyl group by R substituent(s) is preferred. Preferred compounds of Formula IV include N,Nxe2x80x2-disubstituted compounds, i.e. where R2 and R3 are each hydrogen, as well as tri- and tetra-substituted compounds where one or both of R2 and R3 are other than hydrogen. Alkyl such as methyl, ethyl or propyl is a preferred R2 or R3 group. Substituted or unsubstituted aryl such as substituted or unsubstituted phenyl or benzyl are preferred R1 groups.
A particularly preferred group of compounds of Formula IV are those of the following Formula IV(A): 
wherein each Rxe2x80x2 and Rxe2x80x3 are each independepently selected from the same group as defined for R of Formula IV above; R2 and R3 are defined the same as in Formula IV above; and nxe2x80x2 and nxe2x80x3 are each an integer of 1 to 5, and preferably are each 1 or 2; and pharmaceutically acceptable salts thereof. It is preferred that nxe2x80x2 and nxe2x80x3 are each 1, and Rxe2x80x2 and Rxe2x80x3 are each a meta or para substituent, more preferably each being a para substituent. It is further preferred that Rxe2x80x2 and Rxe2x80x3 are each branched substituents such as tert-butyl, sec-butyl, iso-butyl, iso-pentyl and the like. Preferably R2 and R3 are hydrogen or C1-4alkyl such as methyl or ethyl. Specifically preferred compounds of Formula IV(A) include N,Nxe2x80x2-bis(3-sec-butylphenyl)guanidine and N,Nxe2x80x2-bis(4-tert-butylphenyl)guanidine. In another aspect, the invention provides compounds of said Formula IV(A), particularly for use for the methods of treatment disclosed herein, but where excluded from said Formula IV(A) are the compounds of N,Nxe2x80x2-bis(4-neopentylphenyl)guanidine, N,Nxe2x80x2-bis(4-t-butylphenyl)guanidine, N,Nxe2x80x2-bis(4-n-butylphenyl)guanidine, and N,Nxe2x80x2-bis(4-cyclohexylphenyl)guanidine.
Preferred compounds of Formula IV, particularly for use in methods of treatment of the invention, also include those compounds wherein R2 and R3 are taken together to form a substituted or unsubstituted alkylene linkage of from 3 to about 6 carbon atoms, particularly compounds with an alkylene linkage of 3 carbon atoms as represented of the following Formula IV(B): 
wherein R, R1 and n are each the same as defined above for Formula IV, and pharmaceutically acceptable salts thereof. Preferred R1 groups of compounds of Formula IV(B) include substituted and unsubstituted alkaryl, particularly substituted and unsubstituted benzyl, and substituted and unsubstituted carbocyclic aryl, particularly substituted and unsubstituted phenyl, substituted and unsubstituted naphthyl and substituted and unsubstituted acenaphthyl. Preferred substituents of such substituted phenyl, naphthyl or acenaphthyl R1 groups include C1-8alkyl, C1-8alkoxy, C1-8(mono- or dialkyl)amine, alkoxyaryl and carbocyclic aryloxy, such as sec-butyl, tert-butyl, hexyl, butyoxy, phenoxy, benzyloxy, and the like.
Specifically, particularly for use in methods of treatment of the invention, are compounds of the above Formula IV(B) where R1 is a substituted or unsubstituted phenyl, as represented by the following Formula IV(BB): 
where each R and Rxe2x80x2 are each independently halo, hydroxy, amino, nitro, substituted or unsubstituted alkyl having from 3 to about 10 carbon atoms and preferably from 4 to about 10 carbon atoms, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl having 3 to about 10 carbon atoms, or substituted or unsubstituted alkynyl having 3 to about 10 carbon atoms; and
each n and nxe2x80x2 is independently an integer of from 0 to 5, preferably from 1 to 5, more preferably 1 to 2 or 3. Particularly preferred is where each n and nxe2x80x2 is 1. Preferred compounds of Formula IV(BB) include those where one or more R or Rxe2x80x2 substituents is a branched group such as a branched alkyl group e.g. sec-butyl or tert-butyl, or where one or more R substituent is substituted or unsubstituted aralkoxy, particularly substituted or unsubstituted benzyloxy. Para-substitution and meta-substitution of the phenyl group by R and Rxe2x80x2 substituent(s) is typically preferred. Particularly preferred is where n and nxe2x80x2 are each 1, and R and Rxe2x80x2 are each para substituents. Preferred R and Rxe2x80x2 substituents include alkoxy and alkoxyaryl, such as butoxy, pentoxy, hexoxy, substituted and unsubstituted benzyloxy and the like. Specifically preferred compounds of Formula IV(BB) include N,Nxe2x80x2-bis-(alkylphenyl)-2-iminopyrimidazolidine including N,Nxe2x80x2-bis-(butylphenyl)-2-iminopyrimidazolidine, N,Nxe2x80x2-bis-(pentylphenyl)-2-iminopyrimidazolidine, and N,Nxe2x80x2-bis-(hexylphenyl)-2-iminopyrimidazolidine.
The invention also includes compounds of Formulas IV(B) or IV(BB) where two R substituents or two Rxe2x80x2 substituents together form a ring fused to the phenyl ring. Preferred fused rings have 5 to about 7 or 8 ring members and may be a carbocyclic aryl or saturated carbon ring, or a heteroaromatic or heteroalicyclic ring having 1 or 2 N, O or S atoms. Exemplary fused rings include e.g. tetralinyl, indane, or a saturated six carbon ring to form a tetralinyl fused ring.
In another aspect, acenaphthyl-substituted guanidines of the following Formula V are provided: 
wherein:
R is substituted or unsubstituted heteroaromatic containing 1-3 rings, 3 to 8 ring members in each ring and 1-3 heteroatoms;
R1 and R2 are each independently hydrogen, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least 5 ring atoms, substituted or unsubstituted aralkyl having at least 5 ring atoms, or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;
and pharmaceutically acceptable salts thereof.
Preferred R groups of Formula V include 1,2,3,4-tetrahydroquinolinyl, indolinyl, piperonyl, benz[cd]indolinyl and [benz[cd]indo-2[1H]-one. The above depicted acenaphthyl group preferably is substituted by the guanidine nitrogen at the 3-position or 5-position. Preferred compounds of Formula V include N,Nxe2x80x2-disubstituted compounds, i.e. where R1 and R2 are each hydrogen, as well as tri- and tetra-substituted compounds where one or both of R1 and R2 are other than hydrogen. Alkyl such as methyl, ethyl or propyl is a preferred R1 and R2 group of compounds of Formula V.
At least some compounds of the invention may exist as any one of a number of tautomeric forms. Each of these tautomeric forms are within the scope of the invention, including as defined by the formulas specified herein.
The present invention includes methods for treatment and/or prophylaxis of neurological conditions such as epilepsy, neurodegenerative conditions and/or nerve cell death resulting from, e.g., hypoxia, hypoglycemia, brain or spinal chord ischemia, brain or spinal chord trauma, stroke, heart attack, drowning or carbon monoxide poisoning. In this regard, compound of the invention are particularly useful to administer to mammals, particularly humans, susceptible or suffering from stroke or heart attack. Compounds of the invention also are useful to treat and/or prevent various neurodegenerative diseases such as Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Alzheimer""s disease, Down""s Syndrome. Korsakoff""s disease, olivopontocerebellar atrophy, HIV-induced dementia and blindness or multi-infarct dementia. Compounds of the invention also may be used to treat anxiety, e.g. by administration to subjects susceptible to generalized anxiety disorder. Compounds of the invention will have particular utility for treatment of global cerebral ischemia as may occur following cardiac arrest, drowning and carbon monoxide poisoning. Compounds of the invention also may be used to treat other disorders of the nervous system, disorders of the cardiovascular system such as hypertension, cardiac arrhythmias or angina pectoris, endocrine disorders such as acromegaly and diabetes insipidus, as well as use for treatment of chronic pain and as a local anesthetic. Compounds of the invention will have further utility for the treatment of those diseases in which the pathophysiology of the disorder involves excessive otherwise inappropriate (e.g., hypersecretory) cellular secretion, e.g., secretion of an endogenous substance such as a catecholamine, a hormone or a growth factor. Exemplary diseases are specifically discussed infra. Compounds of the invention also will have utility for the treatment of those diseases in which the pathophysiology of the disorder involves excessive or otherwise inappropriate (e.g., hypersecretory) cellular secretion, e.g., secretion of an endogenous substance such as a catecholamine, a hormone or a growth factor. The methods of treatment of the invention (which includes prophylactic therapy) generally comprise administration of a therapeutically effective amount of one or more compounds of the invention to an animal, including a mammal, particularly a human.
Further provided are diagnostic methods comprising use of the compounds of the invention. More specifically, a compound of the invention can be suitably labelled such as by radiolabelling a compound with 125I, tritium, 32P, 99Tc, or the like, preferably 125I. The labelled compound can be administered to a subject such as a human and the subject imaged for a disease or disorder involving ion-channel activity such as stroke.
The invention also provides pharmaceutical compositions that comprise one or more compounds of the invention and a suitable carrier.